Progressive Conduction System Disease Preceding Hypertrophy in IVS4 + 919G > A Fabry Variant: a Population-based...

The IVS4 + 919G > A variant is the most prevalent late-onset Fabry variant in East Asian populations, but its electrophysiological trajectory remains incompletely defined.

From a regional genetic screening program, 905 IVS4 + 919G > A carriers were identified among 457,581 patients and matched 1:2 to controls by age and sex. Electrocardiographic (ECG) parameters were compared across decades, and echocardiography correlated structural changes with ECG findings.

The cumulative prevalence of IVS4 + 919G > A was 0.198%. Age-specific prevalence in females was ∼2.5-fold higher than in males (0.11-0.15%), without significant change throughout different age categories. Female carriers demonstrated the catch-up phenomenon after the age of 60. Males exhibited a 9-fold risk of right bundle branch block (RBBB) and pacemaker implantation (PPM) compared with male controls (RBBB, HR 9.286, 95% CI 5.16-16.70, P < 0.001; PPM, HR 9.197, 95% CI 2.88-29.31, P < 0.001), and this precedes the onset of echocardiographic left ventricular hypertrophy. Risk of stroke and atrial fibrillation (HR 1.435, 95% CI 0.69-2.96, P = 0.289) was similar between male carriers and controls. PR interval was not shortening and prolongs instead. Combining left ventricular hypertrophy with conduction abnormalities, ECG detection achieved 88% sensitivity, exceeding echocardiographic criteria alone (51.5%).

IVS4 + 919G > A variant is characterized by a progressive electrical phenotype dominated by conduction system disease preceding hypertrophy without excess major arrhythmic events. Electrocardiographic surveillance and phenotype-based risk stratification may be more informative than structural assessment alone for identifying individuals at risk of device therapy.